The delivery of therapeutic and pharmaceutical agents is a complex problem without a single universal solution. Many chronic diseases and conditions can be treated effectively by oral medications, but side effects, patient forgetfulness, and other factors often produce high rates of noncompliance with the recommended treatment. In such cases, patient outcomes can be improved using sustained delivery formulations that simplify the medication regimen (e.g., Lupron Depot® for endometriosis).
Where possible, diseases and conditions that affect only a single organ or local tissue are preferably treated by a local application. This allows for a relatively high concentration of the therapeutic agent at the site where it is most needed, and allows for minimal systemic exposure. However there are relatively few tissues that are directly accessible, with skin, hair follicles, the oral, nasal and genitourinary cavities, and eyes being candidates for direct application of therapeutic agents. Direct application of therapeutic agents to internal organs is more challenging, but has been useful in the treatment of some types of tumors.
In the treatment of ocular conditions in particular, many medications are now delivered topically to the eye as eyedrops. Despite the success of the eyedrop in treating diseases and conditions of the eye, treatment with topical eyedrops suffers from numerous drawbacks.
A significant drawback of the eyedrop is the requirement that the pharmaceutical agent be soluble in an isotonic buffered solution at a therapeutically effective concentration and be chemically stable in solution for 18 months or longer. However, solubility of useful therapeutic agents in aqueous formulation is often well below the concentration needed for effective treatment. This can sometimes be corrected by the addition of various excipients, but this increases the complexity of the formulation and often reduces tolerability of the eyedrop.
A second limitation of eyedrops is the rapid clearance of the therapeutic agent via nasolacrimal drainage from the eye surface. This results in most of the compound being delivered to the inside of the nose, where it is not needed and where, in fact, a high concentration of agent might have a detrimental effect.
A third limitation to the use of eyedrops is the observation that many therapeutically-valuable agents cause a local irritation when topically-dosed to the eye. The cornea of the eye is highly sensitive to the application of chemical agents. This irritation potential significantly limits the use of many otherwise valuable therapeutic agents.
A fourth limitation of eyedrops, which also applies to systemic drugs taken by oral, sublingual, nasal or rectal delivery routes, is the need to re-apply the therapeutic agent on a regular basis. For eyedrops, repeating application as frequently as four times a day can be necessary, and even the best agents must be reapplied on a daily basis. For many individuals, in particular the elderly, this frequent dosing becomes burdensome and leads to non-compliance with the dosing regimen, lessening the therapeutic value of the treatment.
To counter these disadvantages of eyedrop delivery, researchers have suggested various devices aimed at providing local delivery over a longer period of time. U.S. Pat. No. 5,824,072 to Wong discloses a non-biodegradable implant containing a pharmaceutical agent that diffuses through a water-impermeable polymer matrix into the target tissue. The implant is placed in the tear film or in a surgically-induced avascular region, or in direct communication with the vitreous.
U.S. Pat. No. 5,476,511 to Gwon et al. discloses a polymer implant for placement under the conjunctiva of the eye. The implant is claimed to be useful for the delivery of neovascular inhibitors for the treatment of age-related macular degeneration (AMD). Again, the pharmaceutical agent diffuses through a water-impermeable polymer matrix of the implant.
U.S. Pat. No. 5,773,019 to Aston et al. discloses a non-biodegradable implant for the delivery of steroids and immunosuppressives such as cyclosporine for the treatment of uveitis, with the drug again diffusing through the water-impermeable polymer matrix of the implant.
U.S. Pat. No. 3,854,480 to Zaffaroni discloses a drug-delivery system with a solid inner matrix formulation containing solid particles of drug surrounded by an outer polymer membrane that is permeable to the passage of the drug. While both the inner matrix and the outer wall are claimed to be permeable to the passage of drugs, the patent requires that the rate of diffusion of the outer membrane be not more than 10% of the rate of the inner matrix.
Both U.S. Pat. No. 4,281,654 to Shell, et al. and U.S. Pat. No. 4,190,642 to Gale, et al. disclose matrix polymer systems that are designed to deliver either beta-blockers or a combination of epinephrine and pilocarpine to the eye to treat glaucoma. Gale, et al. micronize their medicaments to a particle size of not more than 100 microns and these are subsequently dispersed throughout the entire polymer matrix, with no distinct cavity that contains the drug and no drug-free outer layer. In addition, both Shell and Gale require the walls surrounding these small depots be ruptured by the force of the osmotic pressure in order to release the drug by way of those formed ruptures.
All of the above-referenced patents and publications are hereby incorporated herein by reference.